SCYX-7158, a 3,3-dimethyloxaborole-6-carboxamide, is distinguished from earlier trypanocidal oxaboroles by enhanced pharmacokinetic and central nervous system disposition properties allowing for a once per day (QD) oral dosing regimen at a markedly lower efficacious dose in a Stage 2 murine model of Human African Trypanosomiasis (HAT) model. The discovery of SCYX-7158 was achieved through application of integrated lead optimization strategies across the disciplines of medicinal chemistry, parasitology and pharmacokinetics. SCYX-7158 is active in vitro against relevant strains of Trypanosoma brucei, including T. b. rhodesiense and T. b. gambiense, and is efficacious in both Stage 1 and Stage 2 murine HAT models. Physicochemical and in vitro ADME properties of SCYX-7158 are consistent with the compound being orally available, metabolically stable, readily CNS permeable and with low risk for drug-drug interactions. In an ongoing murine Stage 2 study, SCYX-7158 is effective orally at doses as low as 12.5 mg/kg (QD x 7 days). In vivo pharmacokinetic characterization of SCYX-7158 demonstrates that the compound is highly bioavailable in rodents, has low intravenous plasma clearance, a 24 hr elimination half-life and a volume of distribution that indicates good tissue distribution. Most importantly, SCYX- 7158 readily distributes into the brain and cerebrospinal fluid, and crosses the blood-testicular barrier to achieve therapeutically-relevant concentrations in potential trypanosomal sanctuary sites. Based on these properties, which promise lower rates of recrudescence than with current standard care, SCYX-7158 has been selected as a pre-clinical candidate for treatment of Stage 2 HAT.
Jacobs, R.; Nare, B.; Wring, S.; Bacchi, C.; Brun, R.; Plattner, J.; Beaudet, B.; Bowling, T.; Chen, D.; Freund, Y.; Gaukel, E.; Jenks, M.; Kaiser, M.; Mercer, L.; Noe, A.; Orr, M.; Parham, R.; Rewerts, C.; Sligar, J.; Yarlett, N.; Don, R. Efficacy and Pharmacokinetics of SCYX-7158 (AN5568): a Novel and Potent Oxaborole-6-Carboxamide Selected as a Pre-Clinical Candidate for Once-Daily Oral Treatment for Stage 2 Human African Trypanosomiasis. (2009)
Efficacy and Pharmacokinetics of SCYX-7158 (AN5568): a Novel and Potent Oxaborole-6-Carboxamide Selected as a Pre-Clinical Candidate for Once-Daily Oral Treatment for Stage 2 Human African Trypanosomiasis.